Cristiano Ronaldo stole the show in New York City, finishing off a pair of counterattacks with aplomb to send the Spanish side on their way to a victory that they fully warranted.
Angel Di Maria had earlier given Madrid the lead after 25 minutes with a swerving volley, but Robinho stabbed home a surprise equaliser eight minutes later to send the match into the break all square.
However, Ronaldo took over in the second-half with his brace before a late header from Sergio Ramos and a goal from Jose Callejon at the death put matters beyond any doubt.
Karim Benzema and Mesut Ozil were among those handed a start by Mourinho, who fielded a strong group to begin the match, with 22-year old defender Nacho the only unfamiliar name.
Massimiliano Allegri followed suit with his XI, playing a host of regulars, with Kevin-Prince Boateng lining up just behind Robinho and Antonio Cassano to spearhead the Milan attack.
It was Madrid who fired the first warning shot after eight minutes, as a swerving drive by Sami Khedira forced Christian Abbiati into an awkward parry.
The Spanish champions kept Milan under pressure as they continued to look the more threatening side, with their wide players in particular heavily involved early on, despite the narrow Yankee Stadium pitch.
Abbiati was called into action again, first punching clear a dangerous flicked header from Pepe as the Rossoneri struggled to defend a corner, then smothering a low shot from Ronaldo from 20 yards out.
But the Milan keeper could do nothing about Di Maria’s strike after 25 minutes. The Argentine winger attacked a weak clearance from a corner on the edge of the box, ripping an unstoppable volley into the back of the net.
The response Allegri would have hoped for did not come. Milan struggled to get the ball out of their own half, and when they did, were absolutely toothless in attack.
However, that all changed on 33 minutes as out of absolutely nowhere, they were level. A seemingly harmless move was sparked into life by a deft touch from Antonio Nocerino that released Robinho, who poked a classy first-time finish into the corner.
Madrid were back on the offensive, as Ronaldo broke free on goal, but Abbiati was quick off his line to block him just inside the area.
Di Maria was next up, firing in a powerful cross that gave the keeper cause to punch clear as Milan somehow made it into the half on level terms.
However, five minutes after the restart, Madrid restored their advantage. A swift counterattack saw Lassana Diarra lead the charge through the middle, and his pass picked out Ronaldo peeling away to the left. The Portuguese did not hesitate, and lashed home a stinging left-footed finish.
Ronaldo was at it again moments later, forcing substitute keeper Marco Amelia to parry his testing effort low at the near post.
However, Amelia was left stranded in the 56th minute, as a low cross from Ozil somehow squeezed through to Ronaldo, whose blast cannoned back off the post.
Madrid would strike the woodwork once again, with Gonzalo Higuain’s blistering shot from outside the area touching off the bar.
But with 66 minutes gone, the pressure from Los Blancos would finally prove too much for Milan, who were taken apart once again on the counter.
Higuain was the architect, marauding down the right and playing in Kaka at the top of the box, who slipped in Ronaldo with impunity for the finish and Madrid’s third goal of the evening.
That seemed to finally coax Milan out of their shell. Kevin Constant came close with a header from a corner, before Stephan El Shaarawy’s shot was blocked as danger beckoned in front of the Madrid goal.
But the threat was short-lived, as a bullet header by Ramos from a corner made it 4-1 and ended the resistance of Milan once and for all.
Callejon should have extended the lead even further in the 86th minute, but steered his effort wide after being picked out in acres of space inside the box.
But Callejon would not be denied, controlling a Kaka cross as Milan's defence fell apart once again, and lifting over Amelia for the fifth.